Nature publishes a "truly useful" cell atlas: containing more than 300 types of protein kinases found in human cells

Protein kinase, the most important class of enzymes in humans, is a signaling molecule that regulates almost all cellular activities, including growth, cell division, and metabolism
.
Dysfunction of these cellular pathways can lead to a variety of diseases, especially cancer
.

Identifying protein kinases involved in cell dysfunction and cancer development can lead to many new drug targets, but for the vast majority of these kinases, scientists don't know which cellular pathways they are involved in, or what their substrates are
.

"We have a lot of sequencing data for cancer genomes, but what we lack is a large-scale study
of cancer signaling pathways and protein kinase activation states.
If we had this information, we would have a better way of treating specific tumors," said
Michael Yaffe, director of MIT's Center for Precision Cancer Medicine.

Yaffe and other researchers have now created a comprehensive map of protein kinases found in more than 300 species found in human cells and identified the proteins
they may target and control.
This information could help scientists decipher many cell signaling pathways and help them discover what happens
to those pathways when cells become cancerous or treated with specific drugs.

Lewis Cantley, professor of cell biology at Harvard Medical School, and Benjamin Turk, associate professor of pharmacology at Yale School of Medicine, are also senior authors of the paper, which was published today in
the journal Nature.
The paper's lead authors are Jared Johnson, a lecturer in pharmacology at Weill Cornell Medical School, and Tomer Yaron
, a graduate student at Weill Cornell Medical School.

"Rosetta Stone"

The human genome includes more than 500 protein kinases that activate or inactivate other proteins
by labeling a chemical modification called a phosphate group.
For most of these kinases, the proteins they target are unknown, but studies of kinases such as MEK and RAF have yielded new cancer drugs that inhibit these kinases, both of which are involved in cellular pathways
that control growth.

To identify other pathways that regulate abnormalities in cancer cells, the researchers used mass spectrometry to analyze phosphoproteomics, a technique for separating molecules based on their mass and charge, in hopes of finding more phosphorylated proteins
in cancer cells or healthy cells.
However, until now, there has been no easy way to examine mass spectrometry data to determine which protein kinases are responsible for phosphorylating these proteins
.
Because of this, how these proteins are regulated or dysregulated in disease remains unknown
.

"For most of the phosphopeptides being measured, we don't know where they are in
the signaling pathway.
We don't have Rosetta Stone that you can use to look at these peptides and say, that's how the data tells us, and the reason is, for most protein kinases, we don't know what their substrates are
.
”

While a postdoc in Cantley's lab 25 years ago, Yaffe began studying the role of
protein kinases in signaling pathways.
Soon after, Turk joined the lab, and since then, the three of them have spent decades studying the enzymes
in their own research group.

"This collaboration started 25 years ago when Ben was in Lew's lab, and now it's really come together, and it's
largely driven by the work done by Jared and Tomer," Yaffe said.

In this study, the researchers analyzed two classes of kinases, serine kinases and threonine kinases, which make up about 85 percent of the body's protein kinases, based on what structural motifs they place phosphate groups on
.

Using a library of peptides previously created by Cantley and Turk to look for motifs for kinase interactions, the researchers measured how the peptide interacted
with all 303 known serine and threonine kinases.
They also used computational models to analyze the interactions they observed, being able to identify kinases capable of phosphorylating each of the 90,000 known phosphorylation sites that have been reported in human cells, for both types of kinases
.

To their surprise, the researchers found that many kinases with very different amino acid sequences had evolved to bind and phosphorylate the same motifs on their substrates
.
They also showed that about half of the kinases they studied targeted one of the three major primitive classes, while the remaining half targeted one
of about a dozen smaller classes.

Decode the signal network

Yaffe said the new kinase profile could help researchers identify different signaling pathways
between normal cells and cancer cells, or between treated and untreated cancer cells.

"This kinase motif map now helps us decode the signaling network, and we can look at all these phosphorylated peptides and map them to
specific kinases.
"

To demonstrate this approach, the researchers analyzed cells treated with an anti-cancer drug that inhibits a kinase called Plk1, which regulates cell division
.
When they analyzed the expression of phosphorylated proteins, they found that many of the affected proteins were controlled by Plk1, as they expected
.
To their surprise, they also found that the treatment increased the activity
of two kinases involved in the cell's response to DNA damage.

Yaffe's lab is now trying to use this map to find other dysfunctional signaling pathways that drive cancer development, particularly in
certain cancer types where no genetic drivers have been found.

He said: "We can now use phosphoomics to determine whether these pathways are regulated or downregulated in this patient's tumor
.
" In cases where the genes that drive cancer are not obvious, it may identify the signaling pathways
that drive cancer.
”

The research was supported
by the Leukemia and Lymphoma Society, the National Institutes of Health, Cancer Research UK, Brain Tumor Charity, the Charles and Marjorie Holloway Foundation, the MIT Center for Precision Cancer Medicine, and the National Cancer Institute's Koch Institute Support (Core).

Original:

An atlas of substrate specificities for the human serine/threonine kinome